Method and apparatus for multimodal electrical modulation of pain

ABSTRACT

Apparatus and methods for managing pain uses separate varying electromagnetic fields, with a variety of temporal and amplitude characteristics, which are applied to a particular neural structure to modulate glial and neuronal interactions as a mechanism for relieving chronic pain. In another embodiment, a single composite modulation/stimulation signal which has rhythmically varying characteristics is used to achieve the same results as separate varying electromagnetic fields. Also, disclosed is an apparatus and method for modulating the expression of genes involved in diverse pathways including inflammatory/immune system mediators, ion channels and neurotransmitters, in both the Spinal Cord (SC) and Dorsal Root Ganglion (DRG) where such expression modulation is caused by spinal cord stimulation or peripheral nerve stimulation using the disclosed apparatus and techniques. In one embodiment of multimodal modulation therapy, the prime signal may be monophasic, or biphasic, in which the polarity of the first phase of the biphasic prime signal may be either cathodic or anodic while the tonic signal may be either monophasic, or biphasic, with the polarity of the first phase of the biphasic tonic signal being either cathodic or anodic.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and benefit of U. S. ProvisionalApplication Ser. No. 62/135,999,filed Mar. 20, 2015,entitled METHOD ANDAPPARATUS FOR BIMODAL MODULATION IN PAIN MANAGEMENT, and U.S.Provisional Application Ser. No. 62/196,030,filed Jul. 23, 2015,entitledMETHOD AND APPARATUS FOR BIMODAL ELECTRICAL MODULATION IN PAIN, thecontents of which are incorporated by reference herein in their entiretyfor all purposes.

FIELD OF THE INVENTION

This disclosure relates to systems and methods for providing multimodalstimulation of neural structures, and, more specifically, for managingpain with either multiple signals or a single signal having modulatedcharacteristics.

BACKGROUND OF THE INVENTION

The term Spinal Cord Stimulation (SCS) is used to describe an advancedmanagement therapy for chronic pain in which a varying electric field isapplied to the Dorsal section of the spinal Cord (DC) via an electrodearray (or electrode arrays) implanted in the epidural space.Conventional SCS also called tonic, traditionally utilizes an electricfield varying between 40-250 Hz that is directed to a targeted painlocation by overlaying it with a perceived tingling sensation, known asparesthesia, created by the stimulating electric field. This therapy hasbeen clinically utilized for about half a century. The principle mode ofaction is based on the Gate Control Theory formulated by Melzack andWall, although a full understanding of the mechanism has yet to beelucidated. The concept behind tonic SCS is that the paresthesia inducedby the applied varying electric field masks, or “closes the gates to”,pain signals travelling to the brain, however, the relationship betweenfrequency, waveform shape, amplitude and pulse width and the mechanismby which SCS provides an analgesic effect is not fully understood.

SUMMARY OF THE INVENTION

Disclosed herein are apparatus and methods for managing pain in apatient by using multimodal stimulation of neural structures, witheither multiple signals or a single signal having modulatedcharacteristics. Multimodal modulation for pain management, inaccordance with the disclosure, contemplates the use of multipleseparate varying or oscillating electromagnetic fields which areindependently applied via an array of electrodes (referred as contactsor leads) to a particular neural structure using a variety of temporaland amplitude characteristics, to modulate glial and neuronalinteractions as the mechanism for relieving chronic pain. Specifically,disclosed is an apparatus and method for modulating the expression ofgenes involved in diverse pathways including inflammatory/immune systemmediators, ion channels and neurotransmitters, in both the Spinal Cord(SC) and Dorsal Root Ganglion (DRG). In one embodiment, such expressionmodulation is caused by spinal cord stimulation or peripheral nervestimulation. In one embodiment, the amplitudes and frequencies of thesignal or signals used to create the multimodal stimulation of neuralstructures may be optimized for improved pain relief and minimal powerusage in an implantable multimodal signal generator, as describedherein.

According to one aspect, the present disclosure provides a method forstimulating/modulating the interaction between glial cells and neuronsof a subject comprising: A) exposing glial cells and neurons of thesubject to a first stimulus; and B) simultaneously exposing the glialcells and neurons of the subject to a second stimulus; wherein the firststimulus and the second stimulus have at least one uncommon parametertherebetween. In one embodiment, the first stimulus and the secondstimulus comprise electrical signals. In another embodiment, theelectrical signals have different values for any of their respectivefrequency, amplitude, phase or waveform shape

According to another aspect, the present disclosure provides a methodfor stimulating and modulating the interaction between glial cells andneurons of a subject comprising: A) exposing glial cells and neurons ofthe subject to a first stimulus; and B) exposing the glial cells andneurons of the subject to a second stimulus; wherein the first stimulusand the second stimulus have a common parameter therebetween. In oneembodiment, the first stimulus comprises a first varying electric fieldand the second stimulus comprises a second varying electric field. Inanother embodiment, the first varying electric field and the secondvarying electric field are provided by a composite electrical signal. Instill another embodiment, the composite electrical signal may be any ofan amplitude modulated, frequency modulated, summation, or pulse widthmodulated signal.

According to another aspect, the present disclosure provides a methodfor stimulating and modulating the interaction between glial cells andneurons of a subject comprising: A) exposing glial cells and neurons ofthe subject to a first stimulus; and B) simultaneously exposing theglial cells and neurons of the subject to a second stimulus; wherein thefirst stimulus and the second stimulus have a common parametertherebetween. In one embodiment, the first stimulus and the secondstimulus comprise electrical signals having substantially the same ofany of amplitudes, frequencies, phases, or waveform shapes.

According to yet another aspect, the present disclosure provides amethod for stimulating and modulating the interaction between glialcells and neurons of a subject comprising: A) providing lead arrayshaving a plurality of electrode contacts electrically coupleable to anelectrical signal source; B) electrically coupling a first subgroup ofthe plurality of electrode contacts to a first electrical signal source;C) electrically coupling a second subgroup of the plurality of electrodecontacts to a second electrical signal source; D) exposing glial cellsand neurons of the subject to the first electrical signal from the firstsubgroup of electrode contacts; and E) simultaneously exposing the glialcells and neurons of the subject to the second electrical signal fromthe second subgroup of electrode contacts.

According to still another aspect, the present disclosure provides amethod for managing pain in a subject comprising: A) activating glialcells by regulating any of genes for calcium binding proteins,cytokines, cell adhesion or specific immune response proteins withoutthe administration of a pharmacological compound to the subject. In oneembodiment, activating the glial cells comprises exposing the glialcells to a first stimulus which may be a varying electromagnetic field.In another embodiment, activating the glial cells comprises exposing theglial cells to a second stimulus, substantially simultaneously with thefirst stimulus, wherein the second stimulus comprises a second varyingelectromagnetic field. In still another embodiment, the first and secondvarying electromagnetic fields have one of different frequency,amplitude, phase, or harmonic content.

According to yet another aspect, the present disclosure provides amethod for managing pain in a subject comprising: A) lowering athreshold for depolarization of nerve fibers in the subject with a firstvarying electromagnetic field; and B) simultaneously activating glialcells with a second varying electromagnetic field; without theadministration of a pharmacological compound to the subject. In oneembodiment, the first varying electromagnetic field and the secondvarying electromagnetic field have any of different respectivefrequencies, amplitudes, phases or harmonic content. In anotherembodiment, the first and second varying electromagnetic fields may beprovided by either a single electrical signal or by two differentelectrical signals.

According to still another aspect, a method for managing pain in asubject comprises: A) lowering a threshold for depolarization of nervefibers in the subject with a first varying electromagnetic field for afirst period of time; and B) simultaneously modulating glial cellactivity with a second varying electromagnetic field during a secondperiod of time not identical to the first period of time causingdown-regulation of calcium binding protein (cabp1) within the modulatedglial cell.

According to yet another aspect, a method for managing pain in a subjectcomprises: A) lowering a threshold for depolarization of nerve fibers inthe subject with a first varying electromagnetic field for a firstperiod of time; and B) simultaneously modulating glial cell activitywith a second varying electromagnetic field during a second period oftime not identical to the first period of time causing up-regulation ofany of Toll-like receptor 2 (tlr2), Chemokine cxcl16, and Glialmaturation factor (Gmfg) within the modulated glial cells.

According to still another aspect, a method for managing pain in asubject comprises: A) lowering a threshold for depolarization of nervefibers in the subject with a first varying electromagnetic field for afirst period of time; and B) simultaneously modulating glial cellactivity with a second varying electromagnetic field during a secondperiod of time not identical to the first period of time; wherein thevarying electromagnetic fields change synaptic plasticity of neurons andglial cells within the neural structures.

According to yet another aspect, a method for managing pain in a subjectcomprises: A) lowering a threshold for depolarization of nerve fibers inthe subject with a first varying electromagnetic field for a firstperiod of time; and B) simultaneously modulating glial cell activitywith a second varying electromagnetic field during a second period oftime not identical to the first period of time; wherein the firstvarying electromagnetic field is provided by an electric signal havingan amplitude set to a value corresponding to a percentage of a PrimingPerception Threshold (PPT) of the subject, and wherein a second varyingelectromagnetic field is provided by an electric signal having anamplitude set to a value corresponding to a percentage of theparesthesia threshold (PT).

In one embodiment of multimodal modulation therapy, the priming signalmay be monophasic, or biphasic, in which the polarity of the first phaseof the biphasic priming signal may be either cathodic or anodic. Withthis embodiment, the tonic signal may have waveform characteristics thatare different from those of the priming signal. The tonic signal may beeither monophasic, or biphasic, with the polarity of the first phase ofthe biphasic tonic signal being either cathodic or anodic. Biphasicstimulation increases the amount of genes related to glial activation(tlr2 and cxcl16) relative to anodic and cathodic stimulation whilemonophasic cathodic stimulation causes the release of glutamate fromastrocytes. Biphasic stimulation increases the amount of cabp1 relativeto monophasic stimulation (cathodic or anodic). Monophasic stimulation(cathodic or anodic) and biphasic stimulation affect similarly theamount of the immune-related gene cd 68 and the expression of the genecoding for the opioid receptor oprm1.

According to one aspect, the present disclosure provides a method forstimulating/modulating the interaction between glial cells and neuronsof a subject comprising: A) exposing glial cells and neurons of thesubject to a first stimulus; and B) simultaneously exposing the glialcells and neurons of the subject to a second stimulus; wherein the firststimulus and the second stimulus have different respective phasepolarities. In one embodiment, the first stimulus and the secondstimulus comprise electrical signals. In another embodiment, theelectrical signals have different values for any of their respectivefrequency, amplitude, waveform shape, or width in the case ofrectangular waveforms.

According to another aspect, the present disclosure provides a methodfor stimulating and modulating the interaction between glial cells andneurons of a subject comprising: A) providing lead arrays having aplurality of electrode contacts electrically coupleable to an electricalsignal source; B) electrically coupling a first subgroup of theplurality of electrode contacts to a first electrical signal source; C)electrically coupling a second subgroup of the plurality of electrodecontacts to a second electrical signal source; D) exposing glial cellsand neurons of the subject to the first electrical signal from the firstsubgroup of electrode contacts; and E) simultaneously exposing the glialcells and neurons of the subject to the second electrical signal fromthe second subgroup of electrode contacts wherein the first electricalsignal and the second electrical signal have different respective phasecharacteristics.

According to still another aspect, the present disclosure provides amethod for managing pain in a subject comprising: A) activating glialcells during a first time period by regulating any of genes for calciumbinding proteins, cytokines, cell adhesion or specific immune responseproteins; and B) administering a pharmacological substance to thesubject during a second time period not identical to the first time. Inone embodiment, such a pharmacological substance suitable for use withthe disclosed method may comprise a metabotropic or ionotropic glutamatereceptor antagonist such as (S)-4-carboxyphenylglycine (CPG),(RS)-α-methyl-4-carboxyphenylglycine (MCPG), or kynurenic acid (KYA). Inanother embodiment, a suitable pharmacological substance may comprise apotassium channel antagonist, such as 4-aminopyridine (4AP), or analpha-2 adrenergic receptor agonist, such as clonidine, or a calciumchannel agonist such as the ω-conotoxin MVIIC. Such pharmacologicalsubstances can help to activate or deactivate glial cells by modulatingthe release of glutamate, potassium or calcium ions in or out the glialcell. In one embodiment, activating the glial cells comprises exposingthe glial cells to a first stimulus which may be a varyingelectromagnetic field. In another embodiment, activating the glial cellscomprises exposing the glial cells to a second stimulus, substantiallysimultaneously with the first stimulus, wherein the second stimuluscomprises a second varying electromagnetic field. In still anotherembodiment, the first and second varying electromagnetic fields have oneof different frequency, amplitude, phase polarity, relative phase,harmonic content, or width for rectangular waveforms.

According to yet another aspect, the present disclosure provides amethod for managing pain in a subject comprising: A) lowering athreshold for depolarization of nerve fibers in the subject with a firstvarying electromagnetic field; and B) simultaneously modulating glialcell activity with a second varying electromagnetic field; wherein theelectromagnetic fields control the balance of glutamate and glutamine ina calcium dependent manner within the modulated glial cells. In oneembodiment, the first varying electromagnetic field and the secondvarying electromagnetic field have any of different respectivefrequencies, amplitudes, phases, harmonic content, or width forrectangular waveforms. In another embodiment, the first and secondvarying electromagnetic fields may be provided by either a singleelectrical signal or by two different electrical signals.

According to still another aspect, a method for managing pain in asubject comprises: A) lowering a threshold for depolarization of nervefibers in the subject with a first varying electromagnetic field for afirst period of time; and B) simultaneously modulating glial cellactivity with a second varying electromagnetic field during a secondperiod of time not identical to the first period of time wherein thecharacteristics of the varying magnetic fields control any of glialdepolarization, release or uptake of ions, and release of glialtransmitters by the glial cells.

According to yet another aspect, a method for managing pain in a subjectcomprises: A) lowering a threshold for depolarization of nerve fibers inthe subject with a first varying electromagnetic field for a firstperiod of time; and B) simultaneously modulating glial cell activitywith a second varying electromagnetic field during a second period oftime not identical to the first period of time, wherein the firstvarying electromagnetic field is provided by an electric signal having afirst phase polarity portion which stimulates glial cells to releaseglutamate, and wherein a second varying electromagnetic field isprovided by the electric signal having a second phase polarity portionwhich stimulates release of glutamate from astrocytes within the glialcells.

According to still another aspect, a method for managing pain in asubject comprises: A) lowering a threshold for depolarization of nervefibers in the subject with a first varying electromagnetic field for afirst period of time; and B) simultaneously modulating glial cellactivity with a second varying electromagnetic field during a secondperiod of time not identical to the first period of time; wherein themanipulation of any of the frequency, amplitude, waveform, width andphase of electrical signal generating the first and second varyingelectromagnetic fields modulates the behavior of glial cells andinteraction thereof with neurons at the synaptic level.

According to yet another aspect, a method for managing pain in a subjectcomprises: A) modulating glial cells in a subject with a monophasicelectromagnetic signal having cathodic polarity thereof selected tostimulate glial cells to release glutamate; and B) modulating glialcells in a subject with a monophasic electromagnetic signal havinganodic polarity thereof selected to stimulate glial cells to inhibit therelease of glutamate.

According to still another aspect, a method for managing pain in asubject comprises: A) modulating glial cells with an asymmetric biphasicelectromagnetic signal having variable duration of the anodic phasethereof selected to modulate the amount of glutamate released therefrom;and B) modulating glial cells with an asymmetric biphasicelectromagnetic signal having variable duration of the cathodic phasethereof selected to modulate the amount of glutamate released therefrom.

According to yet another aspect, a method for managing pain in a subjectcomprises: A) modulating glial cells with an asymmetric biphasicelectromagnetic signal having variable duration of the cathodic andanodic phases thereof selected to modulate the amount of glutamatereleased therefrom, wherein the electromagnetic fields control thebalance of glutamate and glutamine in a calcium dependent manner withinthe modulated glial cells.

According to yet another aspect, a system is provided comprising asignal generation module and one or more leads. The leads are configuredfor exposing glial cells and neurons simultaneously to a firstelectromagnetic stimulus and a second electromagnetic stimulus. Thesignal generation module is configured for having an operating mode forproviding a first and a second electric signal having at least onecommon parameter therebetween or at least one uncommon parametertherebetween to the one or more leads.

Also disclosed herein is an apparatus comprising a signal generationmodule that is configured for electrically coupling with one or moreleads. Coupling of the apparatus with one or more leads may provide thesystem.

Optionally, the signal generation module comprises at least a first anda second electric signal source or terminal and the one or more leadscomprise at least a first and a second subgroup of electrodes. The firstsubgroup of electrodes can be electrically coupled to the first electricsignal source and/or terminal and the second subgroup of electrodes canbe electrically coupled to the second electric signal source and/orterminal.

Optionally, the signal generation module is configured for having anoperating mode for providing at least first and second electric signalscorresponding to the first and second electromagnetic stimulus asdescribed herein. Optionally, the first and second electric signals havea different frequency.

Optionally, the signal generation module is configured for having anoperating mode for providing electric signals to the electrodescorresponding to the electromagnetic stimulus of any of the methodsdescribed herein.

Optionally, the signal generation module is configured for having anoperating mode for providing a Priming signal to the first subgroup ofelectrodes and, e.g. simultaneously, a Tonic signal to the secondsubgroup of electrodes, e.g. as described herein. The signal generationmodule can be configured for having an operating mode for providing afirst electric signal having a frequency between 200 Hz to 1,500 Hz tothe first subgroup of electrodes, and a second electric signal having afrequency lower than the first electric signal, such as between 20 Hzand 150 Hz, to the second subgroup of electrodes. The signal generationmodule may be configured for having an operating mode for providing apriming signal and a tonic signal with a ration of the frequency of thepriming signal to the tonic signal in the range of 20:1 to 40:1.

Optionally, the signal generation module is arranged for generating acomposite electric signal. The composite electric signal can be a summedsignal of the first and second electric signals. Optionally, the signalgeneration module is arranged for generating a multimodal signal, suchas a frequency-modulated signal or an amplitude modulated signal. Thecomposite signal and/or the multimodal signal can be provided to the oneor more leads.

Optionally, the signal generation module can be configured for having anoperating mode for providing a first electric signal having a frequencyto the first subgroup of electrodes, and a second electric signal havingthe same frequency to the second subgroup of electrodes. The frequencycan be between 500 Hz and 1,500 Hz. Other parameters of the first andsecond electric signals may be different, such as the pulse width and/oramplitude. The first electric signal can be fired synchronously, i.e.simultaneously, with the second electric field, or asynchronously, e.g.with a given time delay, relative to the first electric signal.

As used herein, a signal generation module that is configured for havingan operating mode may comprise a memory module containing instructionsdefining at least an operating mode as described, wherein the operatingmode is optionally a user-selectable operating mode and the memorymodule optionally comprises instructions for additional operating modes.In certain embodiments the signal generation module is configured fordelivering electrical signals to one or more leads as specified.

Optionally, the signal generation module comprises two or more electricsignal sources, such as signal generators, that are independentlycontrollable, and are configured for delivering electric signals withparameters that can be set separately for each of the electric signalsources.

Optionally, the apparatus is a non-implantable, e.g. trialing, systemcomprising a signal generation module comprising at least two signalgenerators configured for delivering electric signals with parametersthat can be set separately for each of the signal generators, forexample a Priming signal and a Tonic signal.

Optionally, an implantable multimodal generator is provided, that isadapted for electrically coupling with one or more leads, or optionallyis coupled with one or more leads. The implantable multimodal generatorcomprises generator circuitry and a housing. The housing canhermetically seal the generator circuitry and can be made of a durablebiocompatible material. The generator has an output interface forestablishing electrical connection with electrodes implemented in one ormore leads, e.g. a first and second terminal for electrically couplingto a first and second subgroup of electrodes implemented on one or moreleads.

Optionally the implantable multimodal generator comprises two or moresignal generators and timer electronic circuitry that can slave one ofthe signal generators to another signal generator, such that a delay canbe produced between signals generated from the at least two signalgenerators.

According to another aspect of the disclosure, an electromagneticstimulation device is provided including an output unit for connectionto at least one electrode array, or a plurality of arrays of electrodes,and a signal generator, wherein the stimulation device is arranged forproviding a multimodal stimulation signal to at least one electrodearray, or a plurality of arrays of electrodes via the output unit. Themultimodal stimulation signal can be an electromagnetic signal. At leastone electrode array is configured for exposing glial cells and neuronsto the multimodal stimulation signal. The electromagnetic stimulationdevice can be a pain treatment device.

Optionally, the electromagnetic stimulation device may have an outputunit that includes a first output for connection to a first lead and asecond output for connection to a second lead. The first lead caninclude a first array of electrodes. The second lead can include asecond array of electrodes.

Optionally, the signal generator is arranged for providing a firstelectric signal to the first output and a second electric signal to thesecond output. The first electric signal and the second electric signalcan differ in a parameter such as amplitude, frequency, phase, phasepolarity, waveform shape, and width. The first electric signal and thesecond electric signal may correspond in a parameter such as amplitude,frequency, phase, phase polarity, waveform shape, and width. The secondelectric signal can be a tonic stimulation signal, and the firstelectric signal can have a frequency higher than the frequency of thetonic stimulation signal.

Optionally, the signal generator is arranged for generating a multimodalelectric signal, such as a frequency modulated signal or an amplitudemodulated signal. The multimodal electric signal can be provided to atleast one electrode.

According to another aspect of the disclosure, a method for operating asignal generation module is provided. The method includes connecting thesignal generation module to one or more leads. The leads can alreadyhave been provided to a body of a subject. The method includesgenerating, using the signal generation module, a first oscillatingelectromagnetic field at least one of the one or more leads andgenerating, using the signal generation module, a second oscillatingelectromagnetic field at least one of the one or more leads. The firstoscillating electromagnetic field and the second oscillatingelectromagnetic field can have at least one uncommon parametertherebetween.

According to another aspect of the disclosure, an electricallyconducting material is provided, such as a metal, e.g. in the form of anelectrode, for use in administering an electromagnetic stimulus into asubject for the treatment of pain. The electromagnetic stimulus caninclude a first electromagnetic stimulus and a second electromagneticstimulus. The first stimulus and the second stimulus may have at leastone uncommon parameter therebetween. The first stimulus and the secondstimulus can be signals, or a composite signal, or multimodal signal asdescribed herein.

Optionally, the first stimulus is a Priming signal and the secondstimulus is a Tonic signal. The first stimulus can have a frequencybetween 200 Hz to 1,500 Hz. The second stimulus can have a frequencylower than the first stimulus, such as between 20 Hz and 150 Hz. Thefrequency of the first stimulus and the frequency of the second stimuluscan have a ratio in the range of 20:1 to 40:1.

According to another aspect of the disclosure, an electromagneticstimulation system comprises a memory for storing a plurality ofmultimodal signal parameter programs; a selection device for selectingone of the plurality of multimodal signal parameter programs; amultimodal signal generator controllable by a selected of the pluralityof multimodal signal parameter programs; and an output unit forconnection to at least one electrode; wherein the stimulation device isconfigured to provide a multimodal stimulation signal generated by themultimodal signal generator in accordance with a selected of themultimodal signal parameter programs to the at least one electrode viathe output unit. The system may further comprise an enclosure ofbiocompatible material surrounding the multimodal signal generator andoutput unit. In one embodiment, the multimodal signal generatorgenerates a first and second electric signals on in an operational modethereof. In one embodiment, the system may be combined with at least oneelectrode comprising at least a first and a second subgroup ofelectrodes, and wherein the first subgroup of electrodes is electricallycoupled to the first electric signal and the second subgroup ofelectrodes is electrically coupled to the second electric signal.

It will be appreciated that any of the aspects, features and optionsdescribed in view of the methods apply equally to the system, signalgeneration module and stimulation device. It will be understood that anyone or more of the above aspects, features and options as describedherein can be combined.

DESCRIPTION OF THE DRAWINGS

The various features and advantages of the present invention may be morereadily understood with reference to the following detailed descriptiontaken in conjunction with the accompanying drawings, wherein likereference numerals designate like structural elements, and in which:

FIG. 1 is a schematic diagram illustrating an apparatus for painmanagement in accordance with an embodiment of the present disclosure;

FIG. 2 illustrates a schematic circuit diagram of an implantablemultimodal modulation device that may be utilized with a system inaccordance with an embodiment of the present disclosure;

FIGS. 3A-B illustrate conceptually electrode arrays that may be utilizedwith a system in accordance with an embodiment of the presentdisclosure;

FIG. 4 illustrates conceptually a pair of traces representing signalsthat may be used in an example of prime multimodal modulation inaccordance with an embodiment of the present disclosure;

FIG. 5 illustrates conceptually a pair of traces representing signalsthat may be used in an example of prime multimodal modulation inaccordance with an embodiment of the present disclosure;

FIG. 6 illustrates conceptually a pair of traces representing signalsthat may be used in an example of prime multimodal modulation inaccordance with an embodiment of the present disclosure;

FIG. 7 illustrates conceptually a pair of traces representing signalsthat may be used in an example of twin multimodal modulation inaccordance with an embodiment of the present disclosure;

FIG. 8 illustrates conceptually a pair of traces representing signalsthat may be used in an example of twin multimodal modulation inaccordance with an embodiment of the present disclosure;

FIG. 9 illustrates conceptually an amplitude modulated signal that maybe utilized for multimodal modulation in accordance with an embodimentof the present disclosure;

FIG. 10 illustrates conceptually a frequency modulated signal, with acarrier frequency larger that the modulating frequency, that may beutilized for multimodal modulation in accordance with an embodiment ofthe present disclosure;

FIG. 11 illustrates conceptually a frequency modulated signal, with acarrier frequency smaller than the modulating frequency, that may beutilized for multimodal modulation in accordance with an embodiment ofthe present disclosure;

FIG. 12 illustrates conceptually a dual combined signal, biphasic pulseexample, that may be utilized for multimodal modulation in accordancewith an embodiment of the present disclosure;

FIG. 13 illustrates conceptually a signal with a continually changingfrequency that may be utilized for multimodal modulation in accordancewith an embodiment of the present disclosure;

FIG. 14 illustrates conceptually the placement of an implantable systemwith a human subject in accordance with an embodiment of the presentdisclosure;

FIG. 15 illustrates conceptually the placement of an implantable systemwith a human subject in accordance with an embodiment of the presentdisclosure;

FIG. 16 illustrates conceptually a graph of results achieved in apre-clinical animal study utilizing systems and methods in accordancewith the present disclosure;

FIGS. 17A-B illustrate conceptually graphs of results achieved in ashort time pilot clinical trial period utilizing systems and methods inaccordance with the present disclosure;

FIG. 18 illustrates conceptually a trace representing a signal having amonophasic cathodic rectangular waveform followed by a interphase delayfor passive charge balance that may be used in accordance with anembodiment of the present disclosure;

FIG. 19 illustrates conceptually a trace representing a signal having amonophasic anodic rectangular waveform followed by a interphase delayfor passive charge balance that may be used in accordance with anembodiment of the present disclosure;

FIG. 20 illustrates conceptually a trace representing a signal having abiphasic symmetric rectangular waveform in which the first phase iscathodic that may be used in accordance with an embodiment of thepresent disclosure;

FIG. 21 illustrates conceptually a trace representing a signal having abiphasic symmetric rectangular waveform in which the first phase isanodic that may be used in accordance with an embodiment of the presentdisclosure;

FIG. 22 illustrates conceptually a trace representing a signal having abiphasic asymmetric rectangular waveform in which the first phase iscathodic and the second, anodic phase, is of smaller amplitude andlonger width in accordance with an embodiment of the present disclosure;

FIG. 23 illustrates conceptually a trace representing a signal having abiphasic asymmetric rectangular waveform in which the first phase isanodic and the second, cathodic phase, is of smaller amplitude andlonger width in accordance with an embodiment of the present disclosure;

FIG. 24 illustrates conceptually a trace representing a signal having abiphasic asymmetric rectangular waveform in which the first phase iscathodic and the second, anodic phase, is of larger amplitude andshorter width in accordance with an embodiment of the presentdisclosure;

FIG. 25 illustrates conceptually a trace representing a signal having abiphasic asymmetric rectangular waveform in which the first phase isanodic and the second, cathodic phase, is of larger amplitude andshorter width in accordance with an embodiment of the presentdisclosure;

FIG. 26 illustrates conceptually a trace representing a signal having abiphasic asymmetric rectangular waveform in which the first phase iscathodic and the second, anodic phase, is of the same width and smalleramplitude;

FIG. 27 illustrates conceptually a trace representing a signal having abiphasic asymmetric rectangular waveform in which the first phase isanodic and the second, cathodic phase, is of the same width and smalleramplitude in accordance with an embodiment of the present disclosure;

FIG. 28 illustrates conceptually a trace representing a signal having abiphasic asymmetric rectangular waveform in which the first phase iscathodic and the second, anodic phase, is of the same width and largeramplitude in accordance with an embodiment of the present disclosure;

FIG. 29 illustrates conceptually a trace representing a signal having abiphasic asymmetric rectangular waveform in which the first phase isanodic and the second, cathodic phase, is of the same width and largeramplitude in accordance with an embodiment of the present disclosure;

FIG. 30 illustrates conceptually a trace representing a signal having abiphasic asymmetric waveform in which the first phase is cathodicrectangular and the second, anodic phase, corresponds to acapacitive-coupled recovery to baseline in accordance with an embodimentof the present disclosure;

FIG. 31 illustrates conceptually a trace representing a biphasicasymmetric waveform in which the first phase is anodic and rectangularand the second, cathodic phase, corresponds to a capacitive-coupledrecovery to baseline in accordance with an embodiment of the presentdisclosure; and

FIGS. 32(a)-(e) illustrate conceptually graphs of experimental resultsindicating how the polarity of the stimulating electromagnetic fieldsignal influences gene expression.

DETAILED DESCRIPTION

The present disclosure will be more completely understood through thefollowing description, which should be read in conjunction with thedrawings. In this description, like numbers refer to similar elementswithin various embodiments of the present disclosure. The skilledartisan will readily appreciate that the methods, apparatus and systemsdescribed herein are merely exemplary and that variations can be madewithout departing from the spirit and scope of the disclosure.

The oscillatory electromagnetic fields applied to neural structuresinduce changes in synaptic plasticity upon modulation of two differentcell populations: Neurons and glial cells. This is concurrent with thewell-known effects on neurons such as action potential generation orblockade by the stimulation of mechanosensitive fibers to mask (or closethe gate to) nociceptive signals travelling to the brain. As such,paresthesia is a byproduct and not a pre-requisite to attain pain reliefduring conventional electrical stimulation. In addition, glial cells areimmunocompetent cells that constitute the most common cell population inthe nervous system and play a fundamental role in the development andmaintenance of chronic neuropathic pain. Glial cells are responsible formonitoring the status of the nervous system by using constant chemicalcommunication with neurons and other glial cells. Microglia are theglial cells in charge of monitoring the brain and spinal cord. Followinga nerve (or brain) injury, these cells become activated and respond toany stimulus that is considered a threat to Central Nervous System (CNS)homeostasis. This activation involves morphological changes in themicroglia accompanied by changes in chemotaxis and phagocytic activity,as well as the release of chemokines and cytokines that induce aresponse from the immune system. It has been shown that microglia arethe CNS immediate responders to injury. Injury also triggers theactivation of astrocytes, glial cells that monitor the synaptic cleftsand thus are involved in synaptic plasticity via the regulation of neuroand glial transmitter molecules and involvement of immune cells forsynaptic pruning. Astrocyte activation and regulation is sustained forlonger time and thus it can be hypothesized that astrocytes play animportant role in changes affecting synaptic plasticity in chronic pain.There is experimental evidence that supports this hypothesis. It isworth noting that at the Peripheral Nervous System (PNS),oligodendrocytes, Schwann cells and satellite glial cells, similar toastroglia, play similar roles.

Calcium ions and phosphorylating processes mediated by ATP play animportant role in glial response to injury. Electrical impulses inducechanges in the concentration of calcium ions in the astrocytes, whichpropagates between astrocytes via calcium waves. This, in turn, signalsthe release of transmitters such as glutamate, adenosine and ATP, evenafter sodium channel blockade, which modulates both neuronalexcitability and synaptic transmission. The presence of an externaloscillatory electrical field then provides a stimulus for glial cells toaffect synapses that have been negatively affected by injury. Theelectrical field provides a priming response that moves the function ofthe synapse towards a normal state.

It is possible to electrically stimulate glial cells as their response(glial depolarization, release/uptake on ions, release of glialtransmitters) depends on the specific parameters such as amplitude,frequency, phase polarity, waveform shape, and width (in the case ofrectangular waveforms) of the stimulation. For example, the release ofglutamate from astrocytes may be modulated in proportion to the amountof anodic current administered during biphasic pulsed stimulation.Monophasic cathodic stimulation of hippocampal astrocytes promotes therelease of glutamate. The introduction of an anodic component decreasesthe amount of glutamate released. Given that the glial cells and neuronsrespond differently to electrical fields, it is then possible todifferentially modulate the response of these cell populations withdistinctively different electrical parameters. This theory sets themechanistic basis of multimodal stimulation. Subthreshold stimulationwith an electromagnetic field set at an optimum frequency, amplitude,waveform, width and phase may modulate the behavior of glial cells andthe way they interact with neurons at the synaptic level. Thus,multimodal modulation provides the ability to control the balance ofglutamate and glutamine in a calcium dependent manner and thepossibility of modulating such balance in the appropriate manner withelectromagnetic fields.

Electromagnetic fields modulate the expression of genes and proteins,which are involved in many processes involving synaptic plasticity,neuroprotection, neurogenesis, inflammation. A full genome analysis ofthe ipsilateral DC and DRG obtained from an animal model of chronicneuropathic pain, in which SCS was applied continuously for 72 hoursprovided findings that were used to develop the multimodal methodologiesdescribed below. The results indicate that the analgesic effect may beinduced at the molecular level in addition to, or independently of, theelectric field blocking or masking nerve signaling. For example, SCSupregulates genes for calcium binding proteins (cabp), cytokines (tnf,il6, il1b, cxcl16, ifg), cell adhesion (itgb) and specific immuneresponse proteins (cd68, tlr2) which are linked to glial activation.Modulation parameters, particularly the oscillation frequency andamplitude, may play an important role in the mode of action.

Multimodal Modulation Methodology

According to one aspect of the disclosure, a method for multimodalmodulation, referred to as “prime” modulation utilizes electrode arrays,with some of the electrodes configured to deliver an electric fieldoscillating at a frequency higher than that typically used in tonicstimulation. The electrical field of this priming signal provides apersistent electrochemical potential that facilitates the stimulation ofnerves by another field that is oscillating at a lower frequency. Thepriming signal lowers the threshold for depolarization of nerve fiberswhile simultaneously modulating glial activation. The priming signalalso lowers the impedance of the stimulated tissue, which allows forbetter penetration of the electric field into the neural tissue. Thefrequent pulsing of the priming signal also contributes to a lowerthreshold for depolarization of nerve fibers via membrane integration ofthe electrical stimulus. Additionally, the priming signal contributes toneuronal desynchronization which is a mechanism that helps with thereestablishment of neuronal circuits that have been unnaturallysynchronized to maintain a nociceptive input into the brain. In thedisclosed prime multimodal modulation technique, a mechanism ofdepolarization is combined with amplitudes lower or slightly higher thanthe Paresthesia Threshold (PT), so the patient may or may not experiencetingling even though tonic stimulation is being applied. A primingsignal provides electrical stimulation at frequencies which willactivate the molecular mechanisms that allow for resetting of thesynaptic plasticity to a state closer to the one previous to centralsensitization induced by injury, thus providing a mechanism for longlasting pain relief. The Priming Frequency (PF) may be set to anyfrequency below 1,500 Hz, but above the tonic frequency. In oneembodiment, the PF may be set to any frequency between 200 Hz to 1,500Hz. When a charged-balanced pulsed rectangular electrical signal, e.g.biphasic symmetric, biphasic asymmetric, capacitor coupled monophasic,is used, the Pulse Width (PW) may be set as low as 10 μs and as large asallowed by the priming frequency. For example, the maximum PW for abiphasic signal with equal PW per phase and a 20 μs interphase delay is395 μs for PF=1,200 Hz or 980 μs for PF=500 Hz. Either a voltage orcurrent controlled signal may be used, although a current controlledsignal may be more desirable as such signal does not depend on temporalimpedance variations in the tissue being stimulated. The amplitude ofthe priming field may be preferably set at a value below a PrimingPerception Threshold (PPT), although setting it at or above the PPT isnot excluded. The PPT may be found by slowly increasing the amplitudewhile feedback is obtained from the subject. Once the onset ofperception is recorded, then the amplitude of the priming signal may bechanged to a value which is a percentage of the PPT (% PPT). With anexemplary PF of 1500 Hz, the signal may be then set for a given time,e.g. 10-30 minutes, before an electric field set at a tonic frequencylower than the PF, e.g. 10 Hz to 1,499 Hz, is applied independently toother electrodes in the lead. In one embodiment, with an exemplary PF of200 Hz, the tonic frequency may be in the range of approximately 10 Hzto 199 Hz, for example. In the prime mode of stimulation, the tonicfrequency will be lower than the priming frequency but is notnecessarily limited to a particular range of frequencies below the primefrequency. The Pulse Width (PW) of a charged-balance, e.g. a biphasicsymmetric, biphasic asymmetric, or capacitor coupled monophasic, pulsedsignal can be as low as 10 μs and as large as allowed by the set tonicfrequency. This PW is set to provide a low duty cycle, which willminimize potential field interference between this field and the primingfield, especially in electrode arrangements that are spatially proximal.Spatial interference of the fields can also be reduced by including anelectronic component in the circuitry that can time the delivery of thetonic signal relative to the priming signal. For example, the primingand tonic signals can be delivered synchronously or asynchronously witha delay therebetween. The signal generation and delivery circuitry mayalso allow for modifying the duty cycles of pulsed width signals andvarious schemes in which the time of initial priming can be varied, aswell as the times in which the priming signal is on or off relative tothe time when tonic signal is delivered. The amplitude of the tonicelectric field, which could be either voltage or current controlled, maybe set above, below or at the paresthesia or perception threshold (PT).PT may be obtained by increasing the amplitude of the signal whilegetting feedback from the patient. The tonic amplitude may then be setto a value corresponding to a percentage of the PT (% PT). In the primemultimodal modulation methods described herein both the priming signaland the tonic signal may be below 1,500 Hz, in one embodiment. Inanother embodiment, the tonic signal may be below 500 Hz. In stillanother embodiment, the tonic signal may be below 100 Hz. In oneembodiment, the ratio of priming signal frequency to tonic signalfrequency may be in the range of 20:1 to 40:1, depending on the specificvalues of the frequencies chosen.

In yet another embodiment of multimodal modulation therapy, the primingsignal may be monophasic, as illustrated in FIG. 18 or 19, or biphasic,as illustrated in FIGS. 20-31, in which the polarity of the first phaseof the biphasic prime signal may be either cathodic or anodic. With thisembodiment, the tonic signal may have waveform characteristics that aredifferent from those of the priming signal. The tonic signal may beeither monophasic, as illustrated in FIG. 18 or 19, or biphasic, asillustrated in FIGS. 20-31, with the polarity of the first phase of thebiphasic tonic signal being either cathodic or anodic.

According to another aspect of the disclosure, a method for multimodalstimulation, referred to as “twin” stimulation utilizes two fields thatare oscillating at the same frequency (F), which may be set to a valuelarger than used conventionally. The rationale is similar to the oneused in the priming scheme, except that a frequency between 500 Hz and1,500 Hz, for example, is used for both signals. In this case, thelikelihood of stimulation via depolarization and gating is decreased. Ina typical application some contacts in the electrode may be set todeliver charge-balanced, e.g. biphasic symmetric, biphasic asymmetric,capacitor coupled monophasic, pulses at a rate of between 1,200 Hz to1,500 Hz, for example, and PW for each phase set in between 10 μs and avalue defined by the frequency of the oscillation and the delay betweenphase changes. For example, for F=1,200 Hz and a delay of 10 μs, themaximum PW is 395 μs. The current or voltage amplitude required forperception threshold (PT) is determined and then the electrical signaldelivered to the stimulator may be set above, below or at this value (%PT). The other contacts may be set to deliver a field of the samefrequency, but PW and amplitude could be different, keeping in mind thatthe PW may be limited by frequency and the delay between phase changes.The second twin field could be fired synchronously, i.e. simultaneously,with the first twin field, or asynchronously, e.g. with a given timedelay, relative to the first twin field.

The techniques disclosed herein may be achieved with minimally invasiveprocedures which are preferred over those that require extensivesurgical intervention and healthcare expenses although in particularcircumstances, a surgical implantation may be required. Electricalstimulation leads, similar to those illustrated in FIGS. 3A-B, can beused, but other designs having a different number of electrodes, size ofthe electrical contact, spacing between contacts, and geometricalarrangement of electrodes within an array may be utilized. In anembodiment, a lead comprises a cylindrical arrangement of multipleelectrodes, e.g. between 4 and 16. The diameter of the lead may be smallenough to allow for percutaneous implantation into the spinal canalusing an epidural needle under standard clinical practice. Theelectrodes are made of biocompatible materials such as iridium-platinumalloys which are also resistant to corrosion. For example, a 50 cm longlead implemented with eight electrodes may have a diameter of 1.35 mm,with each cylindrical electrode having a length of 3.0 mm, and a spacingbetween electrodes of 4.0 mm. Conducting wires may run from theelectrodes to the distal part of the lead into metal connectors. Thewires may be enclosed within a triple-insulated containment made of abiocompatible durable polymer.

In the case of multimodal modulation of the spinal cord, variousmulti-contact leads can be positioned in the epidural space to stimulatethe cell populations already described. In one particular arrangement,the leads can be positioned parallel to each other. FIG. 3A illustratestwo eight-contact electrode arrays that can be used for the disclosedmultimodal modulation techniques. Electrode contacts numbered 1-4 and9-12 (using a traditional numbering of electrode contacts), located atthe top (rostral) region may be used to deliver tonic pulses in themultimodal prime scheme, while eight electrode contacts at the bottom(caudal) numbered 5-8 and 13-16 may be used to deliver the primingpulses. Note that the polarity of the leads can also be customizedduring the programming stage, either as bipolar, monopolar, or guardedcathode configurations. Another example of a possible electrode arrayarrangement is shown in FIG. 3B, in which the tonic electric field issurrounded by the electric field of the priming signal, allowing forpriming of a larger section and tonic delivery in a smaller region. Inanother example, each individual electrode array could be set to deliverthe electric fields parallel to each other.

Other arrangements may be used to stimulate different places along thespinal canal, e.g. the leads do not need to be parallel. For example, inone arrangement, one lead can be dedicated to deliver a signal (prime ortwin) at the spinal cord at a given vertebral level, while the otherprovides a signal either more caudad or cephalad relative to theposition of the other lead. Leads can be in principle located at anyvertebral level in the spinal cord, or could also be positionedperipherally, because the principle behind multimodal modulation appliesto peripheral glial cells that survey the axons.

Systems Components

FIG. 1 illustrates conceptually an embodiment of a non-implantabletrialing system that may be utilized to perform the methods disclosedherein. The system comprises a pair of electrical leads 30 and 32, eachof which may be implemented with an array of electrode contacts, abreakout box 18 and signal generators 17 and 19, as illustrated.Breakout box 18 is electrically coupled to leads 30 and 32 and signalgenerators 17 and 19 through appropriate connectors. The breakout box 18and signal generators 17 and 19 may be placed in an enclosure referredto as an External Trial Stimulator (ETS) system 16. Each of generators17 and 19 deliver a particular signal with parameters that can be setseparately for each other. Each of generators 17 and 19 may have thefunctional characteristics and architecture elements similar togenerator 20 described herein without an exterior enclosure suitable forimplantation into a patient. In one embodiment, system 16 may alsoinclude one or more of the modules described herein with reference toImplantable Multimodal Generator 20 and FIG. 2.

The ETS system 16 is electrically coupled to electrical leads, each ofwhich may be implemented with an array of electrode contacts. In anembodiment, a pair of leads 30 and 32 is coupled to the ETS 16 usingappropriate connectors as illustrated in FIG. 1. In another embodiment,a single lead implemented with an array of electrodes can be used. In aconfiguration for performing prime multimodal modulation, one ofgenerators 17 or 19 may be configured to deliver a priming signal, forexample 1,200 Hz, and the other generator may be configured to deliver atonic signal, e.g. at 50 Hz. The breakout box 18 may be used toreconfigure the delivery of signals to the proper electrode contacts inleads 30 and 32. In the embodiment illustrated in FIG. 1, the electrodecontacts 1-8 in electrode array 30 can be split such that electrodecontacts 1-4 deliver a first signal, e.g. a tonic signal, different thana second signal delivered at electrode contacts 5-8 thereof, e. g. apriming signal. Similarly, electrode contacts 9-16 of electrode array 32may be split such that electrode contacts 9-12 thereof deliver a signalsimilar to that delivered by electrode contacts 1-4 in electrode array30, while electrode contacts 13-16 thereof deliver a signal similar tothat delivered at electrode contacts 5-8 in electrode array 30, asillustrated. In other embodiments either the tonic signal or the primingsignal may be sent to any other combination of electrode contacts.

Implantable Multimodal Generator

FIG. 2 illustrates conceptually a block diagram of the elementscomprising an Implantable Multimodal Generator (IMG) 20. The generatorcircuitry may be hermetically sealed in a housing made of a durablebiocompatible material, such as stainless steel or titanium. Thegenerator 20 has an output interface for establishing electricalconnection with arrays of electrodes implemented within the previouslydescribed leads 30 and 32 that deliver the multimodal signals to glialcells and neurons. In one embodiment, the implantable multimodalgenerator 20 comprises a central processing module 25, a memory module28, a telemetry module 26, a power source module 21, signal generatormodule 23, signal generator module 24, and a Breakout and Delay module22, including the output interfaces thereof.

The central processing module 25 may be implemented with amicroprocessor integrated circuit or may comprise reduced functionalitysmall-scale logic, but, in either implementation includes a wirelesstransceiver functionality that enables bidirectional wirelesscommunication of information with an external programmer unit (notshown) or a user-controlled remote 36.

The memory module 28, which may be implemented with either RAM or ROMmemory, may be used to store a modulation program, executable by centralprocessing module 25, which generates functional information of thegenerator 20. The central processing module 25 is able to store andretrieve information from a memory module 28 as commanded by the user.

The telemetry module 26 is used to communicate via a wireless protocolwith the external programmer unit (or control remote) and includestransceiver circuitry in order to conduct wireless communications withdevices remote from generator 20 according to any number of establishedwireless protocols.

The power source module 21 may comprise a rechargeable battery andelectronic circuity that distributes power from the battery to all theother components in the implantable multimodal generator 20.

The signal generator module 23 comprises electronic circuitry thatallows the delivery of charge-balanced waveforms of any waveshape,including but not limited to biphasic or monophasic pulses, sinusoidaltrains, sawtooth trains, triangle trains, and bursts thereof. In oneembodiment, signal generator module 23 comprises electronic circuitrythat allows the delivery of noise signals, such as white noise, with aconstant power spectral density, or pink noise, with equal energy inoctave intervals, or other noise signals in which the energy within thesignal spectrum is distributed in other patterns. In one embodiment, anoise signal may be used as the priming mechanism in the techniquesdisclosed herein. The signal generator module 23 is able to deliverthese waveforms at frequencies ranging from 1 Hz to 100 kHz. For pulsedelivery, the signal generator module 23 is able to deliver rectangularpulse waves over a range of widths, e.g. as small as 1 μs and as largeas 250 ms, depending on frequency. The signal generator module 23 isfurther capable of generating a range of interphase delays. The signalgenerator module 23 is designed to deliver a signal, with amplitudewhich is either voltage controlled or current controlled, over a rangeof values, e.g. 0 V to 30 V or 0 mA to 30 mA, respectively. The signalgenerator module 23 is also able to generate pulses with a duty cycle.The signal generator module 23 is controlled by the central processingmodule 25 according to parameters selected by the user in an externalprogrammer unit (or control remote). Signal generator module 23 may beimplemented with analog or digital circuitry or a combination thereof.Signal generator module 24 may be structurally and functionally similaror dissimilar to signal generator module 23, and may be independentlycontrolled and programmed.

The breakout and delay module 22 comprises an accurate timer electroniccircuitry that can slave one of signal generator modules 23 or 24 to theother, so that a delay can be produced between signals generatedtherefrom such that a synchronized delivery of such signals can beprogrammed by a user, for example as shown in FIG. 7. The breakout anddelay module 22 also incorporates an electronic circuitry, calledbreakout, that allows for the user to select an option in which theoutput array 1 delivers the a particular signal to all top (rostralduring spinal cord stimulation) electrode contacts of a pair ofelectrode arrays (for example, tonic 50 Hz, 250 μs pulse width, 3.0 mA),while output array 2 delivers a different signal to all bottom electrodecontacts of a pair of electrode arrays (for example, a priming signal of1,200 Hz, 100 μs pulse width, 3.5 mA). An example of this option isshown in FIG. 3A. Another option is one illustrated in FIG. 3B. Thebreakout option can be bypassed. In that case, all contacts in a givenelectrode array will be set at the same modulation parameters asdelivered by, for example, signal generator module 23. All contacts inthe other electrode array will be set to same modulation parameters asdelivered by the other Signal Generator module.

In one embodiment, all or most of the functional blocks of generator 20may be fabricated on a single integrated circuit chip including amicroprocessor and associated memory, wireless transducer and one ormore digital oscillators. Alternatively, the digital oscillators may bereplaced with wave tables having stored therein mathematicaldescriptions of various waveform data values which are convertible intoanalog signals using a digital to analog converter integrated into orassociated with the processor module 25 or signal generator modules 23or 24, depending on their respective implementations. Such wavetablesmay be stored in processor module 25 or memory module 28. In embodimentsthe various modules of IMG 20 may communicate over a central businternal thereto or may have dedicated direct connections therebetween,or any combination thereof.

In one embodiment, IMG 20 or ETS 16 may be programmed by a clinicianusing software that allows control of all the aspects of the system. Thesoftware may be accessible in a computer-based interface called theClinician Programmer (CP) software. The software may be implemented withwireless communication protocols for remote access of the IMG 20 or ETS16. ETS 16 may also be provided with a network port such as a USB ormicro-UBS port for interacting with the CP. In the case of IMG 20, theCP software enables the clinician to communicate with central processingmodule 25 to define a set of parameters, e.g. any of amplitude,frequency, phase, phase polarity, waveform shape, and width (rectangularwaveform), etc., of the signal generated by signal generator modules 23or 24 and to further define the parameters of their relative timing bydefining the operational parameters of breakout and delay module 22.Such defined parameter sets may be stored as one or more configurationprograms in memory module 28 or in memory associated with centralprocessing module 25. In one embodiment, one or more configurationprograms may be stored in memory associated with remote controller 36and the parameters thereof transmittable to IMG 20 via telemetry module26 for control of generator modules 23 or 24 and of breakout and delaymodule 22. The CP software may enable the clinician to further definewhich parameter the patient may control with the remote controller 36and to define any limits on such parameter. For example, the cliniciancan set and store a configuration program #1 with parameters thatprovides prime multimodal stimulation consisting of priming with abiphasic symmetric rectangular pulsed signal set at 1,500 Hz, 200 μs PW,and current-based amplitude set as a % PPT, and a tonic signaldelivering biphasic symmetric rectangular pulses at 50 Hz, 400 μs PW,and current-based amplitude set as a % PT. These signals can bedelivered to a particular set of electrodes in the leads. The cliniciancan also set and store a configuration program #2 that provides twinmultimodal stimulation consisting of asynchronous biphasic symmetricrectangular pulses at 1,500 Hz, one of them at 200 μs PW and the otherat 100 μs PW and each set at its own current-based amplitude set aparticular % PT. These signals can be delivered to a particular set ofelectrodes in the leads which may be different to that used inconfiguration program #1. The system allows for setting and storingadditional configuration programs deemed necessary for the clinician andaccording to the storage capacity of the memory module 28. Limitedcontrol of the multimodal configuration programs may be available to thepatient via a remote controller 36. In one embodiment, the clinician canaccess one or more configuration programs using the CP to control any ofthe parameters of a configuration program already stored in the ETS 16or IMG 20. The patient may be able to browse and/or select any availableconfiguration program with the remote controller 36. The patient may beable to change the current-based amplitude of any particularconfiguration program up to a particular setting determined by the PPTor PT in order to optimize pain relief, for example. Note the remotecontroller 36 may be provided with a simple interface, such as aselector switch, or dial to select the appropriate configurationprogram, or a more sophisticated user interface including a visualdisplay with directional keys or touch sensitive menus.

FIG. 4 illustrates conceptually a pair of traces representing signals 40and 45 used in an example of prime multimodal modulation. Signal 40functions as a priming waveform and may comprise, for example, biphasicrectangular pulses with a frequency of 1,200 Hz, PW=200 μs andinterphase delay of 20 μs. Signal 45 functions as the tonic waveform andmay comprise, for example, biphasic rectangular pulses with a frequencyof 50 Hz, PW=200 μs and interphase delay of 20 μs. In this example, theamplitude of the tonic waveform is set to be larger than the amplitudeof the priming waveform. Signals 40 and 45 have been offset in FIG. 4for visual clarity. Note in FIGS. 4-8 the signals representing the tonicand priming waveforms are offset for visual clarity, such offset notmeant to limiting in any matter.

FIG. 5 illustrates conceptually a pair of traces representing signals 50and 55 used in an example of prime multimodal modulation. Signal 50functions as a priming waveform and may comprise, for example, biphasicrectangular pulses with a frequency of 1,200 Hz, PW=200 μs andinterphase delay of 20 μs. Bottom trace is the tonic waveform and maycomprise, for example, biphasic rectangular pulses with a frequency of50 Hz, PW=200 μs and interphase delay of 20 μs. In this example theamplitude of the tonic waveform is set to be smaller than the amplitudeof the priming waveform. Signals 50 and 55 have been offset in FIG. 5for visual clarity.

FIG. 6 illustrates conceptually a pair of traces representing signals 60and 65 used in an example of prime multimodal modulation. Signal 60functions as a priming waveform and may comprise, for example, biphasicrectangular pulses with a frequency of 1,200 Hz, PW=200 μs andinterphase delay of 20 μs. Bottom trace is the tonic waveform and maycomprise, for example, biphasic rectangular pulses with a frequency of50 Hz, PW=200 μs and interphase delay of 20 μs. In this example theamplitude of the tonic waveform is set to be equal to the amplitude ofthe priming waveform. Signals 60 and 65 have been offset in FIG. 6 forvisual clarity.

FIG. 7 illustrates conceptually a pair of traces representing signals 70and 75 used in an example of twin multimodal modulation. Both signals 70and 75 comprise, for example, biphasic rectangular pulses with afrequency of 1,200 Hz, PW=200 μs and interphase delay of 20 μs. In thisexample, signals 70 and 75 are synchronous to each other and theamplitude of the waveforms is set to be equal. Signal 70 and 75 havebeen offset in FIG. 7 for visual clarity.

FIG. 8 illustrates conceptually a pair of traces representing signals 80and 85 used in an example of twin multimodal modulation. Both signals 80and 85 may comprise, for example, biphasic square pulses with afrequency of 1,200 Hz, PW=200 μs and interphase delay of 20 μs. In thisexample signals 80 and 85 are asynchronous with each other and theamplitude of one of the signals is set to be larger than the other.Signals 80 and 85 in FIG. 8 have been offset for visual clarity.

According to another aspect of the disclosure, the benefits and effectsof multimodal modulation, both the prime multimodal technique and thetwin multimodal technique, as described herein, may be achieved with asingle composite modulation/stimulation signal which has rhythmicallyvarying characteristics, and, therefore, alternating magnetic fieldcharacteristics which achieve the same results as two separate signals.In such an embodiment, a composite signal characterized by typicallyalternating characteristics is utilized to obtain the same stimulationand modulation of the interaction between glial cells and neurons.Techniques for combining the separate signals into a single compositesignal may include amplitude modulation, frequency modulation, signalsumming, and generation of customized signals with any of periodic oraperiodic characteristics. In addition, pulse width modulated signalshaving variably changing harmonic energy content may similarly beutilized to achieve the desired multimodal stimulation of glial andneuronal cells. FIGS. 9-13 illustrate conceptually examples of amplitudemodulated, frequency modulated, dual combined sinusoidal, dual combinedbiphasic rectangular pulse, and frequency changing signals,respectively, that may be utilized for multimodal modulation

In accordance with an embodiment of the present disclosure the centralprocessor module 25 of multimodal generator 20 may access stored numericdata mathematically describing wave shapes for one or more signals andmay generate from such data step functions emulating signals atdifferent frequencies. The processor performs algorithmic manipulationof such data to achieve the desired signal processing results. Digitalto analog converters associated with the central processing module 25may convert the processed signal into a single output having the correctamplitude for coupling to one or both electrodes 30 and 32. In thismanner, the interactive effects of two separate signals may be achievedwith a single electrical signal capable of stimulating/modulating theinteraction between glial cells and neurons in a manner which emulatesthe use of two separate signals. In composite signals emulating afrequency modulated prime multimodal modulation signal, eitherconstituent signal component, e.g. the priming signal or the tonicsignal, may function as the program or carrier signals in a frequencymodulation algorithm. For example, a frequency modulated multimodalsignal can have a carrier frequency larger (e.g. 1,000 Hz) than themodulating frequency (e.g. 50 Hz) resulting in a stimulating signal asillustrated in FIG. 10. In another example, a frequency modulatedmultimodal signal can have a carrier frequency smaller (e.g. 50 Hz) thanthe modulating frequency (e.g. 1,000 Hz) resulting in a stimulatingsignal as illustrated in FIG. 11. In an example of an amplitudemodulated multimodal signal, the carrier frequency can have a carrierpriming frequency of, for example, 1,000 Hz, and a modulating frequencyof, for example, 50 Hz, resulting in a stimulating signal as illustratedin FIG. 9.

FIG. 14 illustrates conceptually another embodiment of an implantablesystem with a human subject in prone position. Shown is an example of animplantable system in which both leads 30 and 32 are positioned abovethe dorsal spinal cord at a particular vertebral level. A programmableimplantable multimodal generator (IMG) 20 is attached to the leads usingconductive cables and is powered by a rechargeable or non-rechargeablelong-life battery contained within the Power Source module 21, withinthe implantable multimodal generator 20. An external battery charger 34may be used for recharging of the generator using inductive, i.e.wireless, charging. A wireless remote control 36, which may beimplemented with any number of wireless communication protocols,including Bluetooth or others, may be used to communicate with IMG 20 toenable a patient's adjustment of parameters at the discretion of thephysician. The system may be programmed using an external programmerunit, such a computer (not shown) that can transmit information to theIMG 20 via wireless communication protocols.

FIG. 15 illustrates conceptually another embodiment of an implantablesystem with a human subject in prone position. Shown is an example of animplantable system, similar to that illustrated with reference to FIG.14 herein, in which leads are positioned in the neighborhood of aperipheral nerve.

EXAMPLE 1

Referring to FIG. 16, an initial pilot study using an animal model forneuropathic chronic pain was carried out (n=29). In this study, aperipheral nerve injury was surgically induced by transecting the tibialand peroneal branches of the sciatic nerve at the point of trifurcationwhile sparing the sural nerve (spared nerve injury, SNI, model). Afterfour days of transection, the subject develops mechanical and thermalhypersensitivity (allodynia), which is considered pain-like behavior.Subjects were implanted with a small cylindrical four-contact leadfitted surgically into their epidural space at the vertebral levelcorresponding to the innervation of the sciatic nerve. At day fourpost-surgery subjects were behaviorally tested using von Frey filaments.These filaments of different tensile strength are used to measure thesensitivity of a skin area affected by the nerve injury to mechanicalstimulation. In the SNI model, the plantar area of the hind pawipsilateral to injury becomes hypersensitive. A hypersensitive subjectwill withdraw its paw upon stimulation with a filament of very lowtensile strength. Mechanical hypersensitivity was evident in theipsilateral hind paw in comparison to the contralateral one, which wasused as a normal behavior control. In a particular example of primemultimodal stimulation, electrode contacts 3 and 4 were connected to acurrent source delivering a charge-balanced biphasic symmetricrectangular pulse oscillating at 1,200 Hz and a PW of 30 μs at anamplitude of 0.1 mA (33% motor threshold, MT). This priming signal wasset on for 10 minutes before a tonic signal was sent simultaneously atelectrode contacts 1 and 2. This tonic signal was a charged balancedbiphasic symmetric rectangular pulse oscillating at 50 Hz, PW of 50 μsand amplitude of 0.2 mA (66% MT). In a particular example of twinmultimodal stimulation, electrode contacts 3 and 4 were connected to acurrent source delivering a charge-balanced biphasic rectangular pulseoscillating at 1,200 Hz and a PW of 30 μs at an amplitude of 0.1 mA (33%motor threshold, MT). This signal was set on for 10 minutes beforeanother charged balanced biphasic rectangular pulse oscillating at samefrequency and PW but different amplitude of 0.2 mA (66% MT) was sentsimultaneously at electrode contacts 1 and 2. In either case, electricalstimulation was on continuously for two hours and behavioral testing formechanical sensitivity was performed every fifteen minutes while thesubject was being stimulated. Behavioral testing was continued everyfifteen minutes after stimulation was turned off for one hour and thenevery hour until three hours post stimulation. FIG. 16 shows the resultsas an average of the various recordings obtained from nine subjects.

Behavioral data indicates that multimodal stimulation improvesmechanical allodynia after fifteen minutes of stimulation with theimprovement lasting for more than one hour after the stimulation isturned off, indicating that there is a residual effect of the appliedfields which suggest modulation of the nervous system.

EXAMPLE 2

In the example, the effect of spinal cord stimulation on gene expressionin the ipsilateral dorsal spinal cord (DC) upon induction of chronicneuropathic pain after peripheral nerve injury was investigated.Specifically, in the example we compared the full genome of one the mostcommonly used rodent model for chronic neuropathic pain (spare nerveinjury, SNI) upon continuous SCS relative to sham animals, i.e. animalsin which pain model was induced, were implanted, but not stimulated.

The full genome microarray kit available for the laboratory rat usedcomprised about 21,000 genes. Enrichment analysis based on clusteringstatistics (using WGCNA) allowed for the identification of modules (orsubsets) that contain genes that are highly correlated to each other interms of biological role. Gene ontology analysis allowed for thegrouping of genes within a module in terms of more specific biologicalprocesses and molecular functionality. Further refinement allows for theidentification of key genes within a particular pathway.

It was found by comparison of the genome of the treated animals that SCSupregulates and down-regulates genes implied in various interrelatedprocesses, as described herein.

Comparative Genomics at the Spinal Cord

Considering that stimulation occurs atop the dorsal region of the spinalcord, we concentrated effort on elucidating the role of genes onmolecular functionality and biological functions associated to thistissue. WGCNA identified that SCS significantly upregulated genesinvolved in activation of the immune system (false discovery rate (FDR)adjusted P-value=0.016); while down-regulating genes that are involvedin phosphorylation and activities related to transmembrane transport(FDR P-value=0.011) as well as regulation of neuronal activity includingregeneration and development. Refinement of the data identified 52 keygenes. Out of these, the following are noteworthy, since they areinvolved in the process of glial activation, immune response andneuronal activity:

Calcium binding protein (cabp1): This gene is down-regulated by SCS. Theprotein associated to this gene regulates calcium-dependent activity ofinositol 1,4,5-triphosphate (ITP) receptors. This receptor is involvedin the signaling between astrocytes via calcium waves, which play a keyrole in the intercellular communication that propagates astrocyteactivation. Down regulation of this gene should diminish the activationof astrocytes that is conducive to synaptic reshaping that develops intoa chronic pain state.

Toll-like receptor 2 (tlr2): This gene is up regulated by SCS. Toll-likereceptor2 is expressed by activated glial cells. This gene is expressedin microglia and astrocytes, but expression in activated microglia islarger than expression in astrocytes. The protein associated to the geneinduces a cascade of events that may lead to the secretion ofanti-inflammatory cytokines, such as IL-10.

Chemokine cxcl16: This gene is up regulated by SCS. This is atransmembrane chemokine which drives the interplay between glial cellsand neurons as a result of stimulus. Cxcl16 is expressed by microgliaand astrocytes as a neuroprotective agent. Up-regulation of this gene bySCS is indicative of a neuroprotective process in the spinal cord likelyinvolving the modulation of microglia.

Glial maturation factor (Gmfg): This gene is up regulated by SCS. Thisgene has been thought to be involved in glial differentiation and neuralregeneration. There is not much known about this gene. Its up regulationby SCS may be associated to glial activation processes that may lead toneuronal regeneration.

Other key genes up-regulated or down-regulated by spinal cordstimulation are described with reference to Table 1-1 below:

TABLE 1-1 Process Gene Description Notes Selected Genes up-regulated bySCS Inflammation and immune Ly86 lymphocyte antigen 86 Cooperate withtoll like response receptor to mediate the innate immune response Cd68Cd68 molecule Phagocytic activities of tissue macrophages Apbb1ipamyloid beta (A4) precursor Signal transduction from Ras proteinactivation to actin cytoskeletal remodeling Casp1 caspase 1 Cleaves IL-1beta Ifi30 interferon gamma inducible MHC class II-restricted antigenprocessing Cd53 Cd53 molecule Mediate regulation of cell development,activation, growth and motility Tnfaip8l2 tumor necrosis factor,Regulator of innate and alpha-induced protein adaptive immunity bymaintaining immune homeostasis Il1b interleukin 1 beta Mediator of theinflammatory response. Induces cyclooxygenase-2 (COX2) to contribute toinflammatory pain. Cxcl17 chemokine (C—X—C motif) May be a chemokineligand 17 regulating recruitment of monocytes and immature dendriticcells Itgb2 integrin, beta 2 Participate in cell adhesion as well ascell-surface mediated signaling Timp1 TIMP metallopeptidase Inhibitorsof the matrix inhibitor 1 metalloproteinases, involved in degradation ofthe extracellular matrix Tnfsf12 Tumor Necrosis Factor Cytokine thatbelongs to the (Ligand) Superfamily, tumor necrosis factor (TNF) ligandfamily. It can induce apoptosis via multiple pathways of cell death in acell type-specific manner. Il2rg Interleukin 2 Receptor, Common subunitfor the Gamma receptors for a variety of interleukins Selected genesdown-regulated by SCS Ion channel regulation Wwp1 WW domain containingE3 Ubiquitinates and promotes ubiquitin protein ligase 1 degradation ofSMAD2 in response to TGF-beta signaling Micu3 Mitochondrial calciumEssential regulator of uptake family mitochondrial calcium uptake underbasal conditions Grin2a Glutamate receptor, Receptor activation requiresionotropic, N-methyl D- binding of glutamate and aspartate 2A glycine,leads to an influx of calcium into postsynaptic region activatingpathways. NMDA receptors have a critical role in excitatory synaptictransmission and plasticity in the CNS. Binding and metabolic AmphAmphiphysin Associated with the pathways cytoplasmic surface of synapticvesicles Gabrg1 Gamma-Aminobutyric Acid Protein encoded by this gene(GABA) A receptor, Gamma 1 is an integral membrane Gabra2Gamma-Aminobutyric Acid protein and inhibits (GABA) A Receptor, Alpha 2neurotransmission by binding to the benzodiazepine receptor and openingan integral chloride channel Gria3 Glutamate receptor, Receptor forglutamate, ionotropic, AMPA 3 functions as ligand-gated ion channel inthe CNS, plays an important role in excitatory synaptic transmissionCell growth Kcna1 Potassium Voltage-Gated Mediates the voltage- Channel,Shaker-Related dependent potassium ion Subfamily permeability ofexcitable membranes Kifc3 Kinesin Family Member C3 Molecular motor thatuse ATP hydrolysis to translocate cargoes along microtubules ATPrelated, Igsf1 Immunoglobulin Thought to participate in thetransmembrane/transporter Superfamily regulation of interactionsactivity between cells Cell regulation Oprm1 Opioid Receptor, Mu 1Principal target of endogenous opioid peptides and opioid analgesicagents such as beta-endorphin and enkephalins.Many of the genes involved in the inflammatory and immune response areassociated to glial activity. Peripheral nerve injury is accompanied byregulation of genes and proteins not only in the site of injury, butalso in the afferent ipsilateral CNS structures such as the DRG and thespinal cord. We recently obtained the proteomics in the spinal cord andDRG of the SNI animal model for neuropathic pain. This study indicatesthat there are transport and translocation of proteins along the axontowards the soma, and then reciprocal protein transport back to theperiphery to induce axon regeneration. Interestingly, the spinal cordpresents with neuroprotective proteins, some associated to glial cellactivation. The activation of glial cells following injury induces acascade of events including an inflammatory and immune response, whichthen develops into peripheral sensitization that is conducive to ectopicfiring of neurons. The alarm eventually extends to the CNS at the levelof the spinal cord, where the microglia would try to protect theintegrity of the system. Eventually, glial cells overreact and inducethe release of factors that reshape the synapses. These changes in thesynaptic plasticity manifest as chronic pain.

The results indicate that electrical stimulation of the spinal cordelicits the regulation of genes and proteins that modulate theinteractions between glial cells and neurons. It is plausible that thesemolecular events produce analgesia.

EXAMPLE 3

The effect of phase polarity on the modulation of genes previouslypresented was carried out using an animal model of chronic neuropathicpain. In this example, tissues from the spinal cord were obtained fromanimals which have been stimulated using a rectangular waveform at afrequency of 50 Hz and a pulse width of 200 μs per phase which wereeither monophasic cathodic, monophasic anodic, or symmetric biphasicwith an initial cathodic polarity. RNA from tissues was extracted andtranscribed into DNA using standard PCR techniques. The amount of DNAwas then quantified and standardized. Based on our previous experiments(example 2) a panel of genes including markers for glial activation(tlr2, cxcl16), calcium-dependent glial processes (cabp1), immune systemactivation (cd68), and an opioid receptor (oprm1) were selected foranalysis.

FIGS. 32(a)-(e) illustrate conceptually graphs of expression of selectedgenes relative to the polarity of the phase used in the stimulationwaveform, including a) Calcium binding protein (cabp1); b) Chemokinecxcl16; c) Toll-like receptor 2 (tlr2); d) Cd68 molecule; and e) Opioidreceptor mu-1 (oprm1). It is evident that the polarity of the signalphase influences the regulation of genes. Biphasic stimulation increasesthe amount of genes related to glial activation (tlr2 and cxcl16)relative to anodic and cathodic stimulation in response to the releaseof glutamate from astrocytes. Biphasic stimulation increases the amountof cabp1 relative to monophasic stimulation (cathodic or anodic).Monophasic stimulation (cathodic or anodic) and biphasic stimulationproduces similar amounts of the immune-related gene cd 68 and expressionof the gene coding for the opioid receptor, oprm1.

EXAMPLE 4

The subject patient was a 55 y/o female patient with diagnosis of FailedBack Surgery Syndrome complaining of severe axial low back painradiating to bilateral lower extremities all the way to the feet forover eight years. Patient failed multiple medical treatments includingphysical therapy, medication management and surgical intervention.

The patient underwent a spinal cord stimulator trial with a conventionalSCS system. Two leads were positioned in the posterior epidural spacewith the tip of the leads located at the junction of T7 and T8. Patientreturned two days later for reprogramming as leads migrated down asconfirmed by x-ray fluoroscopy. After lead repositioning, patientreported paresthesia coverage from torso level down to leg while inprone position. Reprogramming took place while subject wasseating/standing; however patient reported no coverage on back.Treatment seemed to only cover from waist down to legs. Multipleattempts failed to improve the outcome. At the conclusion of the trialwith conventional SCS, the patient reported only 25% relief.

At this point, the multimodal stimulation system was applied with primemodality as described herein. The system was reprogrammed using twoexternal generators. One was set at 70 Hz, 700 μs PW in the uppercontacts of the parallel leads. The other was set for priming at 1,000Hz, 200 μs PW. The patient reported block of paresthesia when the 1,000Hz was on, while the amplitude of the 70 Hz was 3 mA. Amplitude wasincreased slowly until 3.6-3.7 mA when she experienced paresthesia.Amplitude of the 1,000 Hz signal was set at 2 mA when patient went home.Patient reported no pain in the back.

Patient returned two days later for reprogramming of the multimodalstimulation. After reprogramming, patient continued experiencing painrelief without tingling. Particularly important is pain relief in theback. Pain relief was also experienced in the legs, but not in the feet.Paresthesia was also perceived at 3.7 mA when the 1,000 Hz stimulationwas on, and 3.0 mA when was off. Amplitude of the 1,000 Hz signal wasset below 2 mA, which is below the PPT. Patient went home with 2 mA at1,000 Hz and 2.9 mA at 70 Hz. Patient was able to walk well, flexdownward and reported immediate pain relief in the back.

Patient returned four days later. Subject had adjusted the amplitude ofthe 1,000 Hz down to 1.7 mA because she felt muscle fatigue in the back.The amplitude of the 70 Hz was set at 2.3 mA.

In summary of trial:

1. Subject patient did not experienced paresthesias during the four daysof treatment.

2. Patient reported that the Multimodal Prime treatment was superior toTonic treatment.

3. Patient reported no back pain.

4. Sharp/stabbing pain in leg was significantly reduced.

5. Burning sensation in the feet was not alleviated which preventedpatient from long walks.

6. Significant reduction in opioid consumption.

7. She reported about overall 70% pain relief with multimodalstimulation.

EXAMPLE 5

The subject patient was a 70 y/o male diagnosed with radiculopathy.Patient has suffered from condition since for about 17 years. Subjecthas been treated with conventional treatments without clinical success.Pain numerical rate score before treatment was reported as 10, with painin the back radiating to the legs. A pair of SCS trial leads wereimplanted using a non-parallel alignment (i.e. they were offset fromeach other), and a tonic program has been set. Patient reported 70-75%pain relief in the back and 80% pain relief in the leg from theconventional treatment. Patient reported improvement in sleep and adecrease of Vicodin ingestion. Subject reported liking the paresthesiasensation relative to experiencing pain. Patient reported thatdiscomfort in left foot was not being eliminated by treatment.

Patient was then reprogrammed using multimodal stimulation with a primearrangement with a priming parameters set at 1,200 Hz, 150 μs PW and 5.5mA, while low frequency parameters were set at 50 Hz, 400 μs PW and 3.2mA. Patient experienced paresthesia at 3.5 mA.

Patient did not experience pain in back and legs during the followingcouple of days and was able to adjust low frequency up and down as hefelt comfortable with the paresthesias. However, he maintained theamplitude below the paresthesia threshold for most of the time.

In the evening the next day, patient was very active climbing up anddown stairs (an activity he avoided before SCS treatment). Family wasimpressed he could walk as much as he did that day. On the following dayhe was active around the house doing some activities in his yard,particularly handling the garbage. He admitted he overdid activities inthe last couple of days and thus reported pain at night. He ingested 1Vicodin and increased level of low frequency signal to paresthesiasensation and turned it down to go to sleep. He slept well for 7 hours-.Previous nights he had slept very well for about 8-9 hours. On theafternoon of the following day, he reported no pain (score of 0) in bothback and leg and no discomfort or pain in the feet.

Patient likes the fact he can feel paresthesias for reassuring his painrelief, but enjoys being able to have pain relief without having theconstant tingling. Patient was disappointed he was not going to have themultimodal treatment option when permanently implanted.

In summary:

1. Patient did not experience paresthesias most of the time during threedays. He adjusted amplitude of low frequency tonic stimulator to feelparesthesia when pain recurred and adjusted amplitude down toparesthesia-free to maintain pain relief.

2. Patient was able to reduce pain medication ingestion.

3. Patient reported no back pain and no pain in leg and feet. Hereported 100% relief with prime, except when he increased his dailyactivity considerably relative to usual one he had before stimulation.

4. Patient reported significant improvement on sleep habits.

5. Patient indicated he likes the ability of set paresthesia as a way ofreaffirming a stimulation dosage that will guarantee pain relief whenamplitude is then turned down below paresthesia while maintaining painrelief.

EXAMPLE 6

Referring to FIGS. 17A-B, an observational study using human volunteerswas carried out (n=10 ). These subjects were part of a trial period forcommercial spinal cord stimulation systems administered under standardclinical practice. Subjects voluntarily accepted to try multimodalmodulation after they had completed their trial period. Success in atrial period is indicated by pain relief equal or above 50% relative tothe pain numerical rating score (NRS) present before the spinal cordstimulation therapy was commenced. All subjects had been implanted withtwo eight-electrode trial leads. Six of them had leads staggeredrelative to each other and four of them had leads parallel to eachother. Five of the subjects had trialed conventional tonic stimulationsystems (50-70 Hz) and five of them had trialed a high frequency system(10,000 Hz). Two of the subjects failed the trial with conventionaltonic stimulation (50-70 Hz). Nine of the subjects tried multimodalstimulation using the prime modality and one of them tried the twinmodality. Multimodal stimulation was tried for as short as 3 hours andfor as long as 4 days. All the ten subjects successfully triedmultimodal stimulation under the paresthesia or perception threshold(PT). The mean pain relief of the subjects was 71% and all subjectsdeclared to be satisfied with multimodal stimulation therapy.

The reader will appreciate that the multimodal modulation techniquesdescribed herein, including the Prime and Twin modulation techniques, aswell as modulation achieved with a composite signal, e.g. frequency,amplitude, or pulse width modulated, and multi-modal modulation, can beutilized for regulation of genes and proteins that modulate theinteractions between glial cells and neurons as described herein.

As used herein, the term “pharmacological substance” means any tangiblechemical, drug, medicine or therapeutic substance, either synthetic ornaturally occurring, regardless of the form of administration to thesubject, that is administered to the body of the subject.

At various places in the present specification, values are disclosed ingroups or in ranges. It is specifically intended that the descriptioninclude each and every individual sub-combination of the members of suchgroups and ranges and any combination of the various endpoints of suchgroups or ranges. For example, an integer in the range of 0 to 40 isspecifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and aninteger in the range of 1 to 20 is specifically intended to individuallydisclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, and 20.

For purposes of clarity and a concise description, features aredescribed herein as part of the same or separate embodiments, however,it will be appreciated that scope of the concepts may includeembodiments having combinations of all or some of the features describedherein.

It will be obvious to those recently skilled in the art thatmodifications to the apparatus and process disclosed here in may occur,including substitution of various component values or nodes ofconnection, without parting from the true spirit and scope of thedisclosure as defined by the claims set forth herein. For example,although the embodiments described herein disclose primarily the use ofpulsed rectangular signals, other waveform shapes may be similarly usedto obtain the same effects. For example, any of a monophasic pulse wave,charge balanced biphasic pulse wave, charge imbalanced biphasic pulsewave, charge balanced biphasic with delay pulse wave, charge balancedbiphasic fast reversal wave, and charge balanced biphasic slow reversalwave may be utilized as stimulating waveforms in the multimodalmodulation techniques described herein. In addition, other varyingelectromagnetic fields defined by periodic electric signals havingdifferent waveform shapes may be used as well as noise signals and evennon-periodic electric signals having irregular nonrepeating shapes.

What is claimed is: 1.-38. (canceled)
 39. A method for managing pain ina subject comprising: A) activating glial cells by modulating any ofgenes for calcium binding proteins, cytokines, cell adhesion or specificimmune response proteins without the administration of a pharmacologicalsubstance to the subject.
 40. The method of claim 39 wherein thepharmacological substance comprises any of a metabotropic or ionotropicglutamate receptor antagonist, a potassium channel antagonist, analpha-2 adrenergic receptor agonist, or a calcium channel agonist. 41.The method of claim 39 wherein activating the glial cells comprises: A1)exposing the glial cells to a varying electromagnetic field.
 42. Themethod of claim 41 wherein activating the glial cells further comprises:A2) exposing the glial cells to a second stimulus substantiallysimultaneously with the first stimulus.
 43. The method of claim 42wherein the second stimulus is a varying electromagnetic field.
 44. Amethod for managing pain in a subject comprising: A) activating glialcells of a subject during a first time period by regulating any of genesfor calcium binding proteins, cytokines, cell adhesion or specificimmune response proteins without the administration of a pharmacologicalsubstance; and B) administering a pharmacological substance to thesubject during a second time period not identical to the first timeperiod.
 45. The method of claim 44 wherein activating the glial cellscomprises: A1) exposing the glial cells to a first stimulus.
 46. Themethod of claim 45 wherein the first stimulus is a varyingelectromagnetic field.
 47. The method of claim 46 wherein activating theglial cells further comprises: A2) exposing the glial cells to a secondstimulus substantially simultaneously with the first stimulus.
 48. Themethod of claim 47 wherein the second stimulus is a varyingelectromagnetic field.
 49. The method of claim 48 wherein the firstvarying electromagnetic field and the second varying electromagneticfield have one of different respective frequencies and amplitudes.
 50. Amethod for managing pain in a subject comprising: A) lowering athreshold for depolarization of nerve fibers in the subject with a firstvarying electromagnetic field for a first period of time; and B)simultaneously modulating glial cell activity with a second varyingelectromagnetic field during a second period of time not identical tothe first period of time; wherein the characteristics of the varyingelectromagnetic fields control any of glial depolarization, release oruptake of ions, and release of glial transmitters by the glial cells.51. A method for managing pain in a subject comprising: A) lowering athreshold for depolarization of nerve fibers in the subject with a firstvarying electromagnetic field for a first period of time; and B)simultaneously modulating glial cell activity with a second varyingelectromagnetic field during a second period of time not identical tothe first period of time wherein the varying electromagnetic fieldscontrol the balance of glutamate and glutamine in a calcium dependentmanner within the modulated glial cells.
 52. A method for managing painin a subject comprising: A) modulating glial cells with an asymmetricbiphasic electromagnetic signal having variable duration of the cathodicand anodic phases thereof selected to modulate the amount of glutamatereleased therefrom, wherein the electromagnetic signal controls thebalance of glutamate and glutamine in a calcium dependent manner withinthe modulated glial cells.
 53. A method for managing pain in a subjectcomprising: A) lowering a threshold for depolarization of nerve fibersin the subject with a first varying electromagnetic field for a firstperiod of time; and B) simultaneously modulating glial cell activitywith a second varying electromagnetic field during a second period oftime not identical to the first period of time; wherein the firstvarying electromagnetic field is provided by an electric signal having afirst phase polarity portion which stimulates glial cells to releaseglutamate , and wherein a second varying electromagnetic field isprovided by the electric signal having a second phase polarity portionwhich stimulates release of glutamate from astrocytes within the glialcells.
 54. A method for managing pain in a subject comprising: A)modulating glial cells in a subject with a monophasic electromagneticsignal having cathodic polarity thereof selected to stimulate glialcells to release glutamate; and B) modulating glial cells in the subjectwith a monophasic electromagnetic signal having anodic polarity thereofselected to stimulate glial cells to inhibit the release of glutamate.55. A method for managing pain in a subject comprising: A) modulatingglial cells in a subject with an asymmetric biphasic electromagneticsignal having variable duration of an anodic phase thereof selected tomodulate the amount of glutamate released therefrom; and B) modulatingglial cells in the subject with an asymmetric biphasic electromagneticsignal having variable duration of a cathodic phase thereof selected tomodulate the amount of glutamate released therefrom.
 56. (canceled)